Rare Childhood Disease Helping to Unravel How PTEN Mutations Affect Prostate and Other Cancers

Rare Childhood Disease Helping to Unravel How PTEN Mutations Affect Prostate and Other Cancers

Researchers have found a link between the rare childhood disease, called Fanconi anemia, and a major cancer gene, known as PTEN, that is often mutated in brain, uterine, and prostate cancers.

In the study, “The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair,” they show that Fanconi anemia proteins and PTEN work together to repair DNA damage caused by DNA crosslinking agents, a class of drugs that includes some chemotherapies (such as the platinum-based chemotherapy, cisplatin). Their finding suggests that Fanconi anemia proteins may help predict which cancer patients will benefit from such treatments. The study was published in Scientific Reports.

Fanconi anemia is a rare disease characterized by birth defects, bone marrow failure, and an increased risk of cancer. “People often ask why we study such a rare disease,” Niall Howlett, an associate professor of cell and molecular biology at the University of Rhode Island and the study’s lead author, said in a press release. Howlett has been studying Fanconi anemia for nearly 20 years, and believes it important not only because this disease has no cure or effective treatment, but also because a better understanding may help other patients.

One example where Fanconi anemia studies have helped others is in blood transplants. The first blood transplant was performed in a patient with the disease, and safer and more effective blood transplants were made possible due to studies in these patients. Researchers have also found that some genes involved in the development of Fanconi anemia are also involved in hereditary breast and ovarian cancers.

Howlett’s study is another example of how Fanconi anemia studies may have a broader impact.

The researchers knew that Fanconi anemia patients were particularly sensitive to a certain type of chemotherapy, called DNA crosslinking agents. Similarly, cancer patients with PTEN mutations on their tumors are highly responsive to these drugs.

“So we performed an experiment to determine if Fanconi anemia and PTEN were biochemically linked,” Howlett said. “By testing if cells with mutations in the PTEN gene were also sensitive to DNA crosslinking agents, we discovered that Fanconi anemia patient cells and PTEN-deficient cells were practically indistinguishable in terms of sensitivity to these drugs. This strongly suggested that the Fanconi anemia proteins and PTEN might work together to repair the DNA damage caused by DNA crosslinking agents.”

Further experiments demonstrated that PTEN, indeed, interacts with Fanconi anemia proteins to promote DNA repair. Loss of function of either one of these proteins prevents cells from ably repairing damage to their DNA, which — when such loss is evident in cancer cells — might come in handy to patients undergoing treatment with DNA crosslinking agents.

“We can now predict that if a patient has cancer associated with mutations in PTEN, then it is likely that the cancer will be sensitive to DNA crosslinking agents,” Howlett said. “This could lead to improved outcomes for patients with certain types of PTEN mutations.”

Indeed, the researchers concluded, “[O]ur studies, and those of others, continue to raise the prospect of tailored combination chemo- and radiation therapeutic approaches for PTEN-deficient tumors.”